We reported that the host immunogenetic makeup influences the clinical outcome of invasive GAS disease. Specific HLA class II haplotypes conferred strong protection from the severe forms of the invasive disease, while others increased the risk for SSD. We also determined the underlying mechanism for these genetic associations by demonstrating that the presentation of Strep SAgs by the class II DRB1*1501/DQB1*0602 haplotype, which was strongly associated with protection from SSD (P=0.0007), elicited significantly lower inflammatory responses as compared to their presentation by either risk or neutral haplotypes (P<0.0001). Patients with this protective haplotype mounted significantly reduced responses to the GAS SAgs (low responders) and were less likely to develop SSD. By contrast patients who lacked this protective haplotypes or had the DRB1*14/DQB1*0503 risk haplotypes were high responders to the Strep SAgs and were more likely to develop SSD. Thus, HLA class II allelic variations contribute to differences in the severity of invasive GAS disease by regulating inflammatory responses to Strep SAgs. [unreadable] [unreadable] In this supplement proposal we focus on evaluating the role of HLA class II molecules in modulating GAS infection outcome in vivo using HLA transgenic mice carrying disease associated HLA allele/haplotypes. The information that will be generated in these studies will provide an in vivo validation for our epidemiological and in vitro HLA association studies. [unreadable] [unreadable]